This application describes processes and novel products, some of the starting or intermediate materials for which are described in two United States issued patents assigned to the same assignee, Nos. 3,704,314 and 3,668,241.
This invention relates to a new class of chemical compounds which can be described generally as [1-hydroxy-5- indanyloxy(or thio)] alkanoic acids and to the non-toxic, pharmacologically acceptable salt, ester and amide derivatives. It is also an object of this invention to describe methods for the preparation of the [1-hydroxy-5-indanyloxy]- alkanoic acids. Pharmacological studies show that the instant products are effective diuretic and saluretic agents which can be used in the treatment of conditions associated with electrolyte and fluid retention. The instant products are also useful in the treatment of hypertension. In addition, these compounds are able to maintain the uric acid concentration in the body at pretreatment levels or to even effect a decrease in the uric acid concentration.
When administered in therapeutic dosages, in conventional vehicles, the instant products effectively reduce the amount of sodium and chloride ions in the body, lower dangerous excesses of fluid levels to acceptable levels and, in general, alleviate conditions usually associated with edema. In addition, these compounds overcome a major problem associated with many of the presently available diuretics and saluretics. Many of the presently available diuretics and saluretics have a tendency upon administration to induce hyperuricemia which may cause precipitation of uric acid or sodium urate, or both, in the body which may cause from mild to severe cases of gout. The instant compounds of this invention now provide an effective tool to treat those patients requiring diuretic and saluretic treatment without incurring the risk of inducing gout.
The [1-hydroxy-5-indanyloxy(or thio)alkanoic acids (I) of the invention have the following structural formula: ##STR1## wherein A is oxygen or sulfur; R is lower alkyl containing from 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and the like; cycloalkyl, for example, cycloalkyl containing from 3-6 nuclear carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, phenyl or substituted phenyl wherein the substituents are lower alkyl or halo; thienyl or substituted thienyl wherein the substituents are lower alkyl or halo; R.sup.1 is hydrogen, lower alkyl containing from 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and the like, phenyl lower alkyl wherein the lower alkyl contains from 1 to 3 carbon atoms such as benzyl, phenethyl, phenylpropyl and the like, phenyl or substituted phenyl wherein the substituents are lower alkyl or halo; thienyl or substituted thienyl wherein the substituents are lower alkyl or halo; or suitable groups within the above definitions of R and R.sup.1 may be joined together with the carbon atoms to which they are attached to form a cycloalkyl radical containing from 3 to 7 nuclear carbon atoms which may be unsubstituted or lower alkyl substituted, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl and the like; R.sup.2 is hydrogen, aryl, such as phenyl or lower alkyl containing from 1 to 5 carbon atoms or R.sup.1 and R.sup.2, taken together with the carbon atoms to which they are attached, is cycloalkyl, X.sup.1 is hydrogen, methyl or halo such as chloro, bromo, fluoro and the like and X.sup.2 is methyl or halo such as chloro, bromo, fluoro and the like or X.sup.1 and X.sup.2 may be joined to form a hydrocarbylene chain containing from 3 to 4 carbon atoms, for example, trimethylene, tetramethylene, 1,3-butadienylene and the like, and Y is an alkylene or haloalkylene radical having a maximum of 4 carbon atoms which contain from 1-3 linear carbon atoms between the oxy (or thio) and carboxy group, for example, methylene, ethylidene, propylidene, isopropylidene, ethylene, trimethylene, fluoromethylene and the like.
The preferred embodiments of this invention are the (1-hydroxy-6,7-disubstituted-5-indanyloxylacetic acids having the following structural formula: ##STR2## wherein R.sup.5 is hydrogen or phenyl; R.sup.3 is lower alkyl containing from 1 to 3 carbon atoms such as methyl, ethyl, n-propyl or isopropyl, cycloalkyl containing 5 or 6 nuclear carbon atoms such as cyclopentyl or cyclohexyl, phenyl or substituted phenyl wherein the substituents are lower alkyl or halo; thienyl or substituted thienyl wherein the substituents are lower alkyl or halo; and R.sup.4 is hydrogen, lower alkyl containing from 1 to 3 carbon atoms such as methyl, ethyl, n-propyl or isopropyl; R.sup.5 and R.sup.4 are joined to form cycloalkyl, such as, cyclohexyl or R.sup.3 and R.sup.4 may be joined together with the carbon atom to which they are attached to form a cycloalkyl radical containing from 5 to 6 nuclear carbon atoms such as cyclopentyl, cyclohexyl and the like, and X.sup.3 and X.sup.4 are the same or different radicals selected from methyl or chloro and the non-toxic, pharmacologically acceptable salt, ester and amide derivatives. Other groups of preferred compounds within the broad generic disclosure are those compounds (with reference to formula I) in which X.sup.1 and X.sup.2 are the same or different and are methyl or chloro; Y is methylene; A is oxygen; R.sup.2 is hydrogen and
a. R is cycloalkyl and R.sup.1 is lower alkyl; PA1 b. R is lower alkyl and R.sup.1 is hydrogen; PA1 c. R is phenyl and R.sup.1 is lower alkyl; PA1 d. R is substituted phenyl and R.sup.1 is lower alkyl; PA1 e. R is thienyl and R.sup.1 is lower alkyl; PA1 or f. R is substituted thienyl and R.sup.1 is lower alkyl. PA1 a. wherein R is cyclopentyl and R.sup.1 is methyl; PA1 b. wherein R is methyl and R.sup.1 is isopropyl; PA1 c. wherein R is phenyl and R.sup.1 is methyl or ethyl; PA1 d. wherein R is chlorophenyl and R.sup.1 is methyl; PA1 or e. wherein R is thienyl and R.sup.1 is methyl.
Particularly preferred compounds within the seven groups enumerated above are those:
The foregoing class of compounds exhibit particularly good diuretic and saluretic activity and also either maintains the uric acid concentration in the body at pretreatment levels or even causes a decrease in the uric acid concentration.
The [1-hydroxy-5-indanyloxy(or thio)] alkanoic acids and ester (I) wherein Y contains 1 to 3 linear carbon atoms (Y') may be prepared by either of two methods. One method comprises reacting a haloacetic acid or ester thereof of the formula: ##STR3## wherein R.sup.6 is hydrogen or lower alkyl such as methyl, ethyl, and the like and Z is halo such as bromo, chloro, iodo and the like with a suitable 5-hydroxy(or mercapto)-1-indanol (II, infra). The following equation illustrates this reaction: ##STR4## wherein X.sup.1, X.sup.2, R, R.sup.1, R.sup.2, R.sup.6, Y and Z are as defined above. In general, the reaction is conducted in the presence of a base such as an alkali metal carbonate, hydroxide or alkoxide such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium ethoxide and the like. Any solvent which is inert or substantially inert to the reactants and in which the reagents are reasonably soluble may be employed. Acetone, ethanol and dimethylformamide, for example, have proved to be particularly advantageous solvents. The reaction may be conducted at a temperature in the range of from about 25.degree. C. to the reflux temperature of the particular solvent employed. The reaction with the haloacetic acid or ester is generally complete in about 10 to 60 minutes. If the haloacetic acid ester is employed, the ester obtained may be hydrolyzed to the free acid by methods well known to those skilled in the art.
A second method for preparing compounds of formula I wherein R is straight chain alkyl, R.sup.1 is hydrogen, Y is an alkylene or haloalkylene radical having a maximum of 4 carbon atoms which contain from 1-3 linear carbon atoms between the oxy (or thio) and carboxy group, for example, methylene, ethylidene, propylidene, isopropylidene, ethylene, trimethylene, fluoromethylene and the like and X.sup.1, X.sup.2, R.sup.2 and A are as defined above, consists of treating a 1-oxo compound (III supra) with a reducing agent such as sodium or potassium borohydride. The reaction is conducted using water or a mixture of methanol and water as a solvent and employing temperatures of 5.degree. C. to 50.degree. C; the reaction is illustrated as follows: ##STR5##
Those [1-hydroxy-5-indanyloxy-(or thio)]alkanoic acids (Id) wherein the alkylene chain contains 2 linear carbon atoms between the carboxy and oxy (or thio) groups are prepared from their corresponding 5-hydroxy (or mercaptol)- 1-indanols (II) by the reaction of the latter with propiolactone or with an appropriately substituted propiolactone, in the presence of a base such as an aqueous solution of sodium hydroxide, preferably, while heating the solution at reflux temperatures; followed by the acidification of the carboxylate intermediate thus formed to the desired acid. The following equation illustrates the reaction: ##STR6## wherein A, R, R.sup.1, R.sup.2, R.sup.6, X.sup.1 and X.sup.2 are as defined above and M is a cation derived from an alkali metal hydroxide or alkali metal carbonate such as a sodium or potassium cation.
The 5-hydroxy-(or mercapto)-1-indanols (II, supra), which also exhibit diuretic and uricosuric activity, are prepared by treating the correspondingly substituted 5-hydroxy-(or mercapto)-1-indanone (IV) with a reducing agent such as lithium aluminum hydride, sodium bis( 2-methoxy-ethoxy)aluminum hydride and the like in a dry solvent such as ether, tetrahydrofuran, 1,2-dimethoxyethane and the like. The reaction is advantageously conducted at temperatures of 0.degree. C. to 50.degree. C. for from 5 hours to 3 days. The product is generated upon acidification of the reaction mixture with a mineral acid such as hydrochloric acid.
The following equation illustrates this process: ##STR7## wherein A, R, R.sup.1, R.sup.2, X.sup.1 and X.sup.2 are as defined above.
In the case where R.sup.2 is hydrogen and R is not the same as R.sup.1 a mixture of .alpha.- and .beta.-isomers is obtained. The following equation illustrates this process for the reduction of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone to a mixture of .alpha.- and .beta.-isomers of 2-methyl-2-phenyl- 6,7-dichloroindane-1,5-diol: ##STR8##
The resulting isomers are separated by crystallization from suitable solvents.
The 5-hydroxy-(or mercapto)-1-indanones (IV, supra), are prepared by treating the correspondingly substituted 5-lower alkoxy(or lower alkylthio)-1-indanone (V) with an ether cleaving reagent such as aluminum chloride, pyridine hydrochloride, sodium in liquid ammonia and the like. When aluminum chloride is employed, the solvent may be heptane, carbon disulfide, methylene chloride and the like and when pyridine hydrochloride is employed, it is not necessary to employ a solvent. The following equation illustrates this process: ##STR9## wherein A, R, R.sup.1, R.sup.2, X.sup.1, X.sup.2 and R.sup.6 are as defined above.
The 2,2-disubstituted-5-lower alkoxy-(or lower alkyl thio)-1-indanones (V, supra) which exhibit uricosuric activity are prepared by treating a 2-substituted-5-lower alkoxy (or lower alkyl thio)-1-indanone (Va, infra) with a suitable alkylating reagent of the formula: R.sup.1 Z wherein R.sup.1 and Z are as defined above. This reaction is conducted by first treating the 2-substituted-5-lower alkoxy-1-indanone (Va) with a suitable base, for example, an alkali metal hydride such as sodium hydride and the like, or an alkali metal alkoxide, for example, potassium tertiary butoxide and the like. Other bases which may be employed include sodium amide, lithium amide and the like. This basified compound is then treated with the alkylating reagent, R.sup.1 Z. Any solvent which is inert or substantially inert to the reactants employed may be used. Suitable solvents include, for example, 1,2-dimethoxyethane, tertiary butanol, benzene, dimethylformamide and the like. The reaction may be conducted at a temperature in the range of from about 25.degree. C. to about 150.degree. C. In general, the reaction is conducted at a temperature in the range of from about 75.degree. C. to about 90.degree. C.
The following equation illustrates this process: ##STR10## wherein A, R, R.sup.1, R.sup.2, R.sup.6, X.sup.1, X.sup.2, and Z are as defined above.
An alternative method can also be employed to prepare compounds (of formula V) wherein R is phenyl, substituted phenyl, thienyl or substituted thienyl wherein the substituent is lower alkyl or halo. The starting material in this instance is the 2-R.sup.1 compound (Vb) which is reacted first with the strong base, then with a reagent, such as diphenyliodonium halide, or dithienyliodonium halide e.g., the chloride or bromide, as in the following equation: ##STR11## wherein A, R.sup.1, R.sup.2, R.sup.6, X.sup.1, X.sup.2 and Z are as defined above.
The reaction conditions are as described in the route Va .fwdarw. V, supra.
The 2-substituted-5-lower alkoxy (and lower alkyl thio)-1-indanones (Va, supra) employed above may be prepared by several routes. One route comprising treating the 2-substituted- 5-hydroxy-1-indanone with an alkylating agent such as dimethylsulfate or diethylsulfate in the presence of a base such as sodium hydroxide or potassium hydroxide. Other alkylating agents which may be employed include methyl iodide, ethyl iodide and the like employing dimethylformamide as the preferred solvent and as the base, potassium carbonate. The 2-substituted-5-hydroxy-(and 5-mercapto)-1-indanones employed in this particular procedure are known compounds described in U.S. Pat. Nos. 3,668,241 and U.S. 3,704,314.
A second method for preparing the 2-substituted-5-lower alkoxy-(and lower alkyl thio)-1-indanone (Va) comprises the cyclialkylation of a nuclear lower alkoxy (or lower alkyl thio) substituted (2-alkylidenealkanoyl)benzene (VI, infra) by treatment with an electron-acceptor acid, for example, a Lewis acid such as concentrated sulfuric acid, polyphosphoric acid, boron trifluoride and the like. The reaction may be conducted at a temperature in the range of from about 0.degree. C. to about 60.degree. C., in general, the reaction is conducted at ambient temperature. The following equation illustrates this process: ##STR12## wherein A, R, R.sup.2, R.sup.6, X.sup.1 and X.sup.2 are as defined above.
The 2-spiro-5-lower alkoxy-(and lower alkyl thio)- 1-indanones (Vb) are prepared by treating a 2-(.OMEGA.-haloalkyl)- 5-lower alkoxy-(or lower alkylthio)-1-indanone (Vc) with a base, for example, an alkali metal hydride such as sodium hydride and the like in a suitable inert solvent such as 1,2-dimethoxyethane at the reflux temperature of the particular solvent employed. The following equation illustrates this process: ##STR13## wherein A, R.sup.6, X.sup.1, X.sup.2 and Z are as defined above and Y is an integer having a value of from 3 to 6.
Those compounds wherein R and R.sup.2 may be joined to form together with carbon atoms to which they attach a cyclohexyl ring; are prepared by the cyclialkylation of a nuclear lower alkoxy (or lower alkyl thio)substituted cycloalkylidenoyl benzene by treatment with an electron-acceptor acid, for example polyphosphoric acid, boron trifluoride, concentrated sulfuric acid and the like. The following equation illustrates this process: ##STR14## wherein A, R, R.sup.2, R.sup.6, X.sup.1 and X.sup.2 are as defined above.
The nuclear lower alkoxy (and lower alkyl thio) (2-alkylidenealkanoyl)benzenes (VI, supra) employed above may be prepared by one of three methods. One method, limited to the preparation of the nuclear lower alkoxy-(or lower alkyl thio)- 4-(2-methylenealkanoyl)benzenes (VIb), comprises treating a nuclear lower alkoxy-(or lower alkyl thio)-4-alkanoylbenzene (VII) with dimethylamine hydrochloride and paraformaldehyde followed by treatment of the Mannich intermediate (VIII), thus obtained, with aqueous sodium bicarbonate or anhydrous dimethylformamide, either with or without heat, to afford the desired compound, VIb. The following equation illustrates this process: ##STR15## wherein A, R, R.sup.6, X.sup.1 and X.sup.2 are as defined above.
A second method for preparing the nuclear lower alkoxy-(and lower alkyl thio)-2-(alkylidenealkanoyl)benzenes (VIc), comprises treating a nuclear lower alkoxy-(or lower alkyl thio) substituted 1-bromo-cyclohexanoylbenzene (IX, infra) with a dehydrobrominating agent such as lithium bromide, lithium chloride and the like. Suitable solvents for this reaction include dimethylformamide and the like. This reaction is conveniently conducted at a temperature in the range of from about 50.degree. C. to about 120.degree. C. for a period of time of from about 1 hour to about 6 hours. The following equation illustrates this reaction: ##STR16## wherein A, R.sup.6, X.sup.1 and X.sup.2 are as defined above.
A third method for preparing the compounds of formula VI and one limited to the preparation of the homologous 4-(2-alkylidenealkanoyl)benzenes VId, for example, the 4-(2-ethylidene) and 4-(2-propylidene) homologs, comprises treating a nuclear lower alkoxy (or lower alkyl thio) substituted benzene (X, infra) with an appropriate branched chain alkanoyl halide such as 2-methylbutyryl chloride, 2-ethylbutyryl chloride and the like in the presence of a Friedel-Crafts catalyst to afford the corresponding [4-nuclear lower alkoxy (or lower alkyl thio) substituted]alkanoylbenzene (VIIa); which is halogenated and then dehydrohalogenated to afford the 4-(2-alkylidenealkanoyl)-benzene (VId). The following equation illustrates this process: ##STR17## wherein A, R, R.sup.2, R.sup.6, X.sup.1, X.sup.2 and Z are as defined above.
A fourth method for preparing compounds of formula VI, and one limited to the preparation of those compounds wherein R.sup.2 is phenyl, comprises treating a nuclear lower alkoxy (or alkylthio)-4-alkanoylbenzene (VII) with benzaldehyde in a suitable solvent such as water, dimethylsulfoxide and the like in the presence of base such as sodium hydroxide, potassium hydroxide, either with or without heat, to afford the desired compound VIe. The following equation illustrates this process: ##STR18## wherein A, R, R.sup.6, X.sup.1 and X.sup.2 are as defined above.
The [4-nuclear lower-alkoxy (and lower alkyl thio)-substituted]alkanoylbenzenes (VII) are either known compounds or may be prepared by the reaction of an alkanoyl halide with a nuclear lower alkoxy (or lower alkyl thio) substituted benzene (X, infra) in the presence of a Friedel-Crafts catalyst such as aluminum chloride and the like. The reaction solvent and the temperature at which the reaction is conducted are not particularly critical aspects of this reaction inasmuch as any solvent which is inert to the acyl halide and nuclear lower alkoxy (or lower alkyl thio) substituted benzenes may be employed with good results. In this regard, it has been found that methylene chloride is a particularly suitable solvent. The following equation illustrates this reaction: ##STR19## wherein A, R, R.sup.6, X.sup.1, X.sup.2 and Z are as defined above.
The nuclear lower alkoxy (and lower alkyl thio) substituted (1-bromo-cyclohexanoyl)benzenes employed above are prepared by the bromination of the correspondingly nuclear lower alkoxy (or lower alkyl thio) substituted (2-cyclohexanoyl)benzene employing standard brominating conditions. The following equation illustrates this process: ##STR20## wherein A, R.sup.6, X.sup.1 and X.sup.2 are as defined above.
The nuclear lower alkoxy (and lower alkyl thio) substituted cyclohexanoyl benzenes (VIIb) employed above are prepared in a similar manner as described above employing cyclohexanoyl halide in place of the alkanoyl halide described above. The following equation illustrates this reaction: ##STR21## wherein A, R.sup.6, X.sup.1, X.sup.2 and Z are as defined above.
As previously mentioned, the non-toxic, pharmacologically acceptable salts of the acids of Compound I & Ia are within the scope of this invention. These salts include those of alkali metals, alkaline earth metals and amines such as ammonia, primary and secondary amines and quaternary ammonium hydroxides. Especially preferred metal cations are those derived from alkali metals, e.g., sodium, potassium, lithium, and the like and alkaline earth metals, e.g., calcium, magnesium, and the like and other metals, e.g., aluminum, iron and zinc. These salts are prepared by conventional methods well known in the art. Thus, the acid upon reaction with alkali metal and alkaline earth metal hydroxides, carbonates, bicarbonates, amines or quarternary ammonium hydroxides, forms the corresponding alkali metal, alkaline earth metal, amine or quaternary ammonium salt.
Pharmaceutically acceptable salts can be formed from ammonia, primary, secondary, or tertiary amines, or quaternary ammonium hydroxides such as methylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, .alpha.-phenethylamine, ethylenediamine, piperidine, 1-methylpiperazine, morpholine, pyrrolidine, 1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, N-methylglucosamine, ephedrine, procaine, tetramethylammonium hydroxide, tetraethylammonium hydroxide, benzyltrimethylammonium and the like.
The salts mentioned above are particularly useful as parenteral solutions because they are very soluble in pharmaceutical carriers such as water or alcohol.
The anhydride derived from the carboxylic acids of Formula I are included in the invention.
Also included within the scope of this invention are the ester and amide derivatives of the instant products which are prepared by conventional methods well known to those skilled in the art. Thus, for example, the ester derivative may be prepared by the reaction of a 1-hydroxy-5-indanyloxy-(or thio)-alkanoic acid of this invention with an alcohol, for example, with a lower alkanol. The amide derivatives may be prepared by converting a 1-hydroxy-5-indanyloxy-(or thio)-alkanoic acid to its corresponding acid chloride by treatment with thionyl chloride followed by treating said acid chloride with ammonia, an appropriate mono-lower alkyl amine, di-lower alkyl amine or a hetero amine, such as piperidine, morpholine and the like, to produce the corresponding amide compound. These and other equivalent methods for the preparation of the ester and amide derivatives of the instant products will be apparent to one having ordinary skill in the art and to the extent that said derivatives are both non-toxic and physiologically acceptable to the body system, said derivatives are the functional equivalent of the corresponding [1-hydroxy-5-indanyloxy-(or thio)] alkanoic acids.
In addition, to the salts, esters and amides being functionally equivalent to the carboxylic products, those compounds wherein the carboxylic acid is replaced by a 5-tetrazolyl radical are also functionally equivalent to the carboxylic acids. These tetrazole analogs are prepared as depicted in the following equation: ##STR22## wherein A, R, R.sup.1, R.sup.2, X.sup.1, X.sup.2 and Z are as defined above.
The 5-hydroxy-1-indanone (IV) is treated with a haloacetonitrile sch as chloroacetonitrile, bromoacetonitrile or iodoacetonitrile in the presence of a base such as potassium carbonate and the like in a suitable solvent such as acetone, dimethylformamide, dimethoxyethane and the like at a temperature in the range of from 25.degree. C. to 100.degree. C. to afford the corresponding nitrile (XI, supra) which, upon treatment with sodium azide and ammonium chloride in dimethylformamide at a temperature in the range of from 25.degree. C. to 100.degree. C., affords the 5-(1-oxo-5-indanyloxymethyl)-tetrazole (XII, supra) which, upon reduction with a metal borohydride or sodium bis(2-methoxyethoxy)aluminum hydride affords the 5(1-hydroxy-5-indanyloxymethyl)tetrazole (XIII, supra).
The instant compounds (I) herein disclosed contain one or more asymmetric carbon atoms (i.e. at positions 1,2 and 3 of the indanyl ring). When this situation exists diasteriomers may be separated by methods well known to those skilled in the art and the optical antipodes may be separated by methods described below. This invention embraces, therefore, not only the racemic [1-hydroxy-5-indanyloxy(or thio)]alkanoic acids but also their optically active antipodes.
Separation of the optical isomers of the racemic acids (I) may be accomplished by forming a salt of the racemic mixture with an optically active base such as (+) or (-) amphetamine, (-)-cinchonidine, dehydroabietylamine, (+) or (-)-.alpha.-methylbenzylamine, (+) or (-)-.alpha.-(1-naphthyl)-ethylamine, brucine or strychnine and the like in a suitable solvent such as methanol, ethanol, 2-propanol, benzene, acetonitrile, nitromethane, acetone and the like. There is thus formed in the solution two diastereomeric salts one of which is usually more soluble in the solvent than the other. Repetitive recrystallization of the crystalline salt generally affords a pure diasteriomer. The optically pure [1-hydroxy-5-indanyloxy(or thio)]alkanoic acid is obtained by acidification of the salt with a mineral acid, extraction into ether, evaporation of the solvent and recrystallization of the optically pure antipode.
The other optically pure antipode may generally be obtained by using a different base to form the diastereomeric salt. It is of advantage to isolate the partially resolved acid from the filtrates of the purification of the one diastereomeric salt and to further purify this substance through the use of another optically active base.
Alternatively, the intermediate 5-indanols (II) may be separated into their pure diastereomers and resolved to their pure antipodes before conversion to the instant products (I).
The examples which follow illustrate the [1-hydroxy-5-indanyloxy(or thio)]alkanoic acid products (I) of the invention and the methods by which they are prepared. However, the examples are illustrative only and it will be apparent to those having ordinary skill in the art that all of the products embraced by formula I, supra, may also be prepared in an analogous manner by substituting the appropriate starting materials for those set forth in the examples.